SYDNEY—Professor Cynthia Shannon Weickert at Neuroscience Research Australia (NeuRA) has identified immune cells in greater amounts in the brains of some people with schizophrenia. The study, published on September 13th in Molecular Psychiatry, has the potential to transform schizophrenia research and open new opportunities for developing targeted immune cell therapies.

The study challenges the long held assumption that immune cells are independent of the brain in psychiatric illness, and points at an exciting breakthrough. “We identified immune cells as a new player in the brain pathology of schizophrenia,” said Professor Shannon Weickert.

Until now schizophrenia research focused on the status of three brain cells: the neurons; the glial cells, which support the neurons; and the endothelial cells, which coat the blood vessels. New molecular techniques have allowed the team to identify a fourth cell, the macrophage — a type of immune cell in the brain tissue of people with schizophrenia who show high levels of inflammation.

“Immune cells have previously been ignored as they had long been viewed simply as travelers just thought to be passing by, undertaking surveillance work. They have never been a suspect until now. To find immune cells along the blood brain barrier in increased amounts in people with schizophrenia is an exciting discovery,” explained Shannon Weickert. “It suggests immune cells themselves may be producing these inflammatory signals in the brains of people living with schizophrenia.”

“Soluble intercellular adhesion molecule-1 (sICAM1) was measured in the plasma of 78 patients with schizophrenia/schizoaffective disorder and 73 healthy controls. We found that sICAM1 was significantly elevated in schizophrenia. An efflux transporter, ABCG2, was lower, while mRNAs encoding VE-cadherin and ICAM1 were higher in schizophrenia brain. The ‘high inflammation’ schizophrenia subgroup had lower ABCG2 and higher ICAM1, VE-cadherin, occludin and interferon-induced transmembrane protein mRNAs compared to both ‘low inflammation’ schizophrenia and ‘low inflammation’ control subgroups…People with high levels of cytokine expression and schizophrenia display changes consistent with greater immune cell transmigration into brain via increased ICAM1, which could contribute to other neuropathological changes found in this subgroup of people,” says the study.

“We have observed in people with schizophrenia, the glial cells, one of the local residents, become inflamed and produce distress signals which change the status of the endothelial cells,” Shannon Weickert noted. “We think this may cause the endothelial cells to capture the immune cells when they travel by. These cells may transmigrate across the blood brain barrier, entering the brain in greater amounts in some people with schizophrenia compared to people without the disorder.”

Professor Peter Schofield, CEO of NeuRA, said this innovative new research has the ability to alter the way in which we may be able to diagnose and treat schizophrenia. “This breakthrough demonstrates the value of the NSW Government’s support for Professor Shannon Weickert as NSW Chair of Schizophrenia Research, which has delivered new insights that the community seeks,” Schofield pointed out.

“In our study, transcript levels of CD16, a marker of natural killer cells and activated macrophages/monocytes, CD163 a marker of perivascular macrophages and CD14, a marker of monocytes were all elevated in schizophrenia cases with high inflammation,” states the article. “CD163+ macrophages were detected in the brain vasculature in all cases irrespective of diagnosis and inflammation. Our study now confirms that monocytes can also be found in the prefrontal cortex of individuals with schizophrenia and for the first time, identifies brain tissue macrophages proximal to neurons in over 40% of individuals with schizophrenia who are in a high inflammatory state.”

“The stress from a lifetime of mental illness may contribute to inflammation in the brain in our chronically ill cohort. While peripheral cortisol levels can be elevated in schizophrenia, glucocorticoid receptor mRNA levels are also dysregulated in the brains of people with schizophrenia. When using changes in cortical glucocorticoid and immune pathways to stratify subgroups, we find an overlap in the population of people with schizophrenia in an elevated inflammatory state and in the sample of people with schizophrenia in an elevated stress state. Further research is required to disentangle the reciprocal role of inflammation and stress in the neuropathology of schizophrenia,” the article also mentions.

The research shows that specific immune cells are in the brains of some people with schizophrenia in close enough proximity to the neurons to do damage. Shannon Weickert is encouraging a cross-collaborative approach between neuroscientists and immunologists globally, to work together to develop treatments targeting this abnormal immune pathology of schizophrenia.

“This opens whole new avenues for therapy, because it suggests the pathology of schizophrenia could be within the immune cells and the immune cells could be contributing to the symptoms of schizophrenia,” she concludes.